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Design, Synthesis and Biological Evaluation of N -phenylindole Derivatives as Pks13 Inhibitors against Mycobacterium tuberculosis.
- Source :
-
Molecules . May2022, Vol. 27 Issue 9, p2844-2844. 19p. - Publication Year :
- 2022
-
Abstract
- Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis (Mtb), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb. The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole N moieties. Thirty-six N-phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure–activity relationship (SAR) studies resulted in the discovery of the potent Compounds 45 and 58 against Mtb H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound 58 displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of Mtb and provides a novel scaffold for developing leading anti-TB compounds. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 27
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- Molecules
- Publication Type :
- Academic Journal
- Accession number :
- 156876806
- Full Text :
- https://doi.org/10.3390/molecules27092844